Effect of Lidocaine and Amiodarone on Transmural Heterogeneity of Ventricular Repolarization in Isolated Rabbit Hearts Model of Sustained Global Ischemia

Summary： To study the effect of of lidocaine and amiodarone on the transmural heterogeneity of ventricular repolarization in isolated rabbit hearts model of sustained global ischemia and to explore the mechanisms underlying the antiarrhythmic activity of lidocaine and amiodarone, rabbits were randomly divided into 4 groups： control group, ischemia group, lidocaine group and amiodarone group. By the monophasic action potential （MAP） recording technique, MAPs of epicardium, midmyocardium and endocardium were simultaneously recorded across the left ventricular free wall in rabbit hearts perfused by low-flow ischemia （2. 5 mL/min） in Langendorff method to study the transmural dispcrsion of repolarization （TDR） and arrhythmic induced by ischemia.Our results showed that TDR of three myocardial layers in ischemia group were significantly lengthened after ischemia. TDR was increased from 17.5±3.9 ms to 31.2±4.6 ms at the time that concided with the onset of sustained ventricle arrhythmic. Amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia, and no significant difference was found at other ischemia time points. 5 cases had ventriclar arrhythmia in ischemia group （62. 5%）, but no case in lidocaine group （P〈0.01） and only 1 case in amiodarone group had ventrilar arrhythmia （P〈 0.01）. No significant difference was found between amiodarone group and lidocaine group. It is concluded that TDR of of three myocardial layers increases significantly at ischemia and it is closely associated with development of ventricular arrhythmia, and amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia and has no effects at other ischemia time points.

Ventricular repolarization markers for predicting malignant arrhythmias in clinical practice

Malignant cardiac arrhythmias which result in sudden cardiac death may be present in individuals apparently healthy or be associated with other medical conditions. The way to predict their appearance represents a challenge for the medical community due to the tragic outcomes in most cases. In the last two decades some ventricular repolarization(VR) markers have been found to be useful to predict malignant cardiac arrhythmias in several clinical conditions. The corrected QT, QT dispersion, Tpeak-Tend, Tpeak-Tend dispersion and Tp-e/QT have been studied and implemented in clinical practice for this purpose. These markers are obtained from 12 lead surface electrocardiogram. In this review we discuss how these markers have demonstrated to be effective to predict malignant arrhythmias in medical conditions such as long and short QT syndromes, Brugada syndrome, early repolarization syndrome, acute myocardial ischemia, heart failure, hypertension, diabetes mellitus, obesity and highly trained athletes. Also the main pathophysiological mechanisms that explain the arrhythmogenic predisposition in these diseases and the basis for the VR markers are discussed. However, the same results have not been found in all conditions. Further studies are needed to reach a global consensus in order to incorporate these VR parameters in risk stratification of these patients.

Early repolarization syndrome: A cause of sudden cardiac death

Early repolarization syndrome(ERS), demonstrated as J-point elevation on an electrocardiograph, was formerly thought to be a benign entity, but the recent studies have demonstrated that it can be linked to a considerable risk of life- threatening arrhythmias and sudden cardiac death(SCD). Early repolarization characteristics associated with SCD include high-amplitude J-point elevation, horizontal and/or downslopping ST segments, and inferior and/or lateral leads location. The prevalence of ERS varies between 3% and 24%, depending on age, sex and J-point elevation(0.05 m V vs 0.1 m V) being the main determinants.ERS patients are sporadic and they are at a higher risk of having recurrent cardiac events. Implantable cardioverter-defibrillator implantation and isoproterenol are the suggested therapies in this set of patients. On the other hand, asymptomatic patients with ERS are common and have a better prognosis. The risk stratification in asymptomatic patients with ERS still remains a grey area. This review provides an outline of the up-to-date evidence associated with ERS and the risk of life- threatening arrhythmias. Further prospective studies are required to elucidate the mechanisms of ventricular arrhythmogenesis in patients with ERS.

Effects of hypokalemia on transmural dispersion of ventricular repolarization in left ventricular myocardium

Objective:To observe effects of hypokalemia on transmural heterogeneity of ventricular repolarization in left ventricular myocardium of rabbit,and explore the role of hypokalemia in malignant ventricular arrhythmia（MVA）.Methods:A total of 20 rabbits were randomly divided into control group and hypokalemic group.Isolated hearts in the control group were simply perfused with modified Tyrode’s solution,and were perfused with hypokalemic Tyrode’s solution in hypokalemic group.Ventricular fibrillation threshold（VFT）,90%monophasic action potential repolarization duration(APD90) of subepicardial,midmyocardial and subendocardial myocardium,transmural dispersion of repolarization（TDR） and Cx43 protein expression in three layers of myocardium were measured in both groups.Results:VFT in the control group and the hypokalemic group were（13.40±2.95） V,and（7.00±1.49） V,respectively.There was a significant difference between two groups（P【0.01）.APD90 of three myocardial layers in the hypokalemic group were significantly prolonged than those in the control group（/’【0.01）.△APD90in the hypokalemic group and the control group were（38.10±10\29） ms and（23.7015.68） ms,and TDR were（52.90r 14.55） ms and（36.10±12.44） ms,respectively.△APD90 and TDR in the hypokalemic group were significantly higher than those in the control group(P【0.05|,and the increase in△APD90 of midmyocardium was more significant in the hypokalemic group.Cx43 protein expression of all three myocardial layers were decreased significantly in the hypokalemic group（P【0.01）, and△APD90 was significantly increased {P【0.05).Reduction of Cx43 protein expression was more significant in the midmyocardium.Conclusions:Hypokalemic can increase transmural heterogeneity of Cx43 expression and repolarization in left ventricular myocardium of rabbit,and decrease VFT and can induce MVA more easily.

Relationship between Ambient Fine Particles and Ventricular Repolarization Changes and Heart Rate Variability of Elderly People with Heart Disease in Beijing, China

Objective To explore the effects of particulate matters less than 2.5 μm in aerodynamic diameter （PM2.5） on heart repolarization/depolarization and heart rate variability （HRV）. Methods We conducted a panel study for elderly subjects with heart disease in Beijing from 2007 to 2008. PM2.5 was measured at a fixed station for 20 h continuously each day while electrocardiogram （ECG） indexes of 42 subjects were also recorded repeatedly. Meteorological data was obtained from the China Meteorological Data Sharing Service System. A mixed linear regression model was used to estimate the associations between PMz.s and the ECG indexes. The model was adjusted for age, body mass index, sex, day of the week and meteorology. Results Significant adverse effects of PM2.5 on ECG indexes reflecting HRV were observed statistically and the strongest effect of PM2.s on HRV was on lag i day in our study. However, there were no associations between PM2.5 and ECG indexes reflecting heart repolarization/depolarization. Additionally, the effects of PM2.5 on subjects with hypertension were larger than on the subjects without hypertension. Conclusion This study showed ambient PM2.5could affect cardiac autonomic function of the elderly people with heart disease, and subjects with hypertension appeared to be more susceptive to the autonomic dysfunction induced by PM2.5.

Dispersion of ventricular repolarization: Temporal and spatial

Repolarization heterogeneity(RH)is an intrinsic property of ventricular myocardium and the reason for T-wave formation on electrocardiogram(ECG).Exceeding the physiologically based RH level is associated with appearance of life-threatening ventricular arrhythmias and sudden cardiac death.In this regard,an accurate and comprehensive evaluation of the degree of RH parameters is of importance for assessment of heart state and arrhythmic risk.This review is devoted to comprehensive consideration of RH phenomena in terms of electrophysiological processes underlying RH,cardiac electric field formation during ventricular repolarization,as well as clinical significance of RH and its reflection on ECG parameters.The formation of transmural,apicobasal,left-toright and anterior-posterior gradients of action potential durations and end of repolarization times resulting from the heterogenous distribution of repolarizing ion currents and action potential morphology throughout the heart ventricles,and the different sensitivity of myocardial cells in different ventricular regions to the action of pharmacological agents,temperature,frequency of stimulation,etc.,are being discussed.The review is focused on the fact that RH has different aspects–temporal and spatial,global and local;ECG reflection of various RH aspects and their clinical significance are being discussed.Strategies for comprehensive assessment of ventricular RH using different ECG indices reflecting various RH aspects are presented.

Ibutilide and novel indexes of ventricular repolarization in persistent atrial fibrillation patients

AIM: To examine the effect of ibutilide on novel indexes of repolarization in patients with persistent atrial fibrillation (AF). METHODS: We studied consecutive patients scheduled for elective electrical cardioversion. Intravenous ibutilide (1+1mg) was administered before the electrical cardioversion while close electrocardiographic (ECG) monitoring was performed. ECG indexes such as corrected QT interval (QTc), the interval from the peak until the end of T wave (Tpe), and the Tpe/QT ratio were measured before ibutilide infusion and 10 min after the end of infusion. RESULTS: The final study population consisted of 20 patients (mean age: 67.1±9.9 years, 10 men). Six patients were cardioverted pharmacologically and did not proceed to electrical cardioversion. Two patientsdeveloped short non-sustained episodes of torsades de pointes ventricular tachycardia. All but one of the aforementioned ECG indexes increased significantly after ibutilide administration. In specific, the QTc interval increased from 442 ± 29 to 471 ± 37 ms (P=0.037), the Tpe interval in precordial leads from 96 ms (range 80-108 ms) to 101 ms (range 91-119 ms) (P=0.021), the Tpe interval in lead Ⅱ from 79 ms (range 70-88 ms) to 100 ms (range 87-104 ms) (P<0.001), the Tpe/QT ratio in precordial leads from 0.23 ms (range 0.18-0.26 ms) to 0.26 ms (range 0.23-0.28 ms) (P=0.028), and the Tpe interval dispersion from 25 ms (range 23-30 ms) to 35 ms (range 27-39 ms) (P=0.012). However, the Tpe/QT ratio in lead II did not change significantly. CONCLUSION: Ibutilide increases the duration and dispersion of ventricular repolarization. The prognostic value of Tpe and Tpe/QT in the setting of drug-induced proarrhythmia needs further study.

Ventricular repolarization measures for arrhythmic risk stratification

Ventricular repolarization is a complex electrical phenomenon which represents a crucial stage in electrical cardiac activity. It is expressed on the surface electrocardiogram by the interval between the start of the QRS complex and the end of the T wave or U wave(QT). Several physiological, pathological and iatrogenic factors can influence ventricular repolarization. It has been demonstrated that small perturbations in this process can be a potential trigger of malignant arrhythmias, therefore the analysis of ventricular repolarization represents an interesting tool to implement risk stratification of arrhythmic events in different clinical settings. The aim of this review is to critically revise the traditional methods of static analysis of ventricular repolarization as well as those for dynamic evaluation, their prognostic significance and the possible application in daily clinical practice.

Experimental Study of the Effect of Autonomic Nervous System on the Transmural Dispersion of Ventricular Repolarization under Acute Myocardial Ischemia in Vivo

Summary: The effect of the autonomic nerves on the transmural dispersion of ventricular repolarization (TDR) under acute myocardial ischemia in intact canine was investigated. Using the monophasic action potential (MAP) recording technique, MAPs of the epicardium (Epi), midmyocardium (Mid) and endocardium (Endo) were recorded simultaneously by specially designed plunge-needle electrodes at the left ventricular free wall under acute myocardial ischemia in 12 open-chest dogs. MAPD 90 and TDR among three myocardial layers as well as the incidence of the early afterdepolarization (EAD) before autonomic nervous stimulation and during autonomic nervous stimulation were compared. It was found that 10 min after acute myocardial ischemia, TDR was increased from 55±8 ms to 86±15 ms during sympathetic stimulation (P<0.01). The TDR (53±9 ms) during parasympathetic stimulation was not significantly different from that of the control (55±8 ms) (P>0.05). The EAD was elicited in the Mid of 2 dogs (16 %) 10 min after acute myocardial ischemia, but the EAD were elicited in the Mid of 7 dogs (58 %) during sympathetic stimulation (P<0.01). It was concluded that: (1) Sympathetic stimulation can increase the transmural dispersion of repolari-zation and induce early afterdepolarizations in the Mid under acute myocardial ischemia, which provide the opportunity for the ventricular arrhythmia developing; (2) Parasympathetic stimulation has no significant effect on the transmural dispersion of repolarization under myocardial ischemia.

Effect of Autonomic Nervous System on the Transmural Dispersion of Ventricular Repolarization in Intact Canine

The effect of the autonomic nerves on the transmural dispersion of ventricular repolarization in intact canine was investigated. By using the monophasic action potential (MAP) recording technique, monophasic action potentials (MAPs) of the epicardium (Epi), midmyocardium (Mid) and endocardium (Endo) were recorded simultaneously by specially designed plunge needle electrodes at the left ventricular free wall in 12 open chest dogs. MAPD 90 and transmural dispersion of repolarization among three myocardial layers as well as the incidence of the EAD before autonomic nervous stimulation and during autonomic nervous stimulation were compared. The results showed that the MAPD 90 of Epi, Mid and Endo before autonomic nervous stimulation were 278±11 ms, 316±16 ms and 270±12 ms respectively, the MAPD 90 of Mid was significantly longer than that of Epi or Endo ( P <0.01). MAPD 90 of Epi, Mid and Endo were shortened by 19±4 ms, 45±6 ms, 18±3 ms respectively during sympathetic stimulation. Compared with that of the control, the transmural dispersion of repolarization during sympathetic stimulation was shortened from 44±4 ms to 15±3 ms ( P <0.01), but early afterdepolarizations were elicited in the Mid of 5 dogs (41 %) during sympathetic stimulation. Parasympathetic stimulation did not significantly affect the MAPD 90 in the three layers. It is concluded that there is the transmural dispersion of ventricular repolarization in intact canine. Sympathetic stimulation can reduce transmural dispersion of repolarization, but it can produce early afterdepolarizations in the Mid. Parasympathetic stimulation does not significantly affect the transmural dispersion of ventricular repolarization.

12-lead electrocardiogram features of arrhythmic risk: A focus on early repolarization

The 12-lead electrocardiogram(ECG) is still the most used tool in cardiology clinical practice. Considering its easy accessibility, low cost and the information that it provides, it remains the starting point for diagnosis and prognosis. More specifically, its ability to detect prognostic markers for sudden cardiac death due to arrhythmias by identifying specific patterns that express electrical disturbances of the heart muscle, which may predispose to malignant arrhythmias, is universally recognized. Alterations in the ventricular repolarization process, identifiable on a 12-lead ECG, play a role in the genesis of ventricular arrhythmias in different cardiac diseases. The aim of this paper is to focus the attention on a new marker of arrhythmic risk, the early repolarization pattern in order to highlight the prognostic role of the 12-lead ECG.

The Effects of Na^+/Ca^(2+) exchange (NCX) on the Repolarization of Canine Ventricular Myocyte-Potential Arrhythmogenic Effect of NCX during a Mis-matched Repolarization and Relaxation Xiamen Zhongshan Hospital, Xiamen Medical College, Xiamen University

Objective Background and Objects: Naturally occurring temporal variability of action potentialduration (APD) in isolated myocytes has been noted. Most of the studies have beenfocusing on analyzes of the differences in ionic channels and currents among theepicardial-, mid-myocardial-(M) and endocardial myocytes, and the rate-dependent (adaptation) characteristics of APD. We have found that the change in APD during achange in frequency of stimulation mostly reflects a change in rate of repolarization at distinct membrane potential levels. We assumed that in the myocytes, there is balancing mechanism, which is constantly adjusting the various ionic currents accommodating to the changing conditions. This intrinsic ability of adaptation is important and may offer some of the consequences of the transmural heterogeneity in adaptation of APD. This adaptive behaviors maybe equally important in maintaining the normal electrophysiological properties and in induction of arrhythmia in a case of error in normal adaptation. Though most studies of Na +/Ca 2+ exchange (NCX) has been emphasized on its reverse activaty during pathyological condition. Our hypothesis is that reverse activaty of NCX also plays an important role in adjusting the repolarization of AP during a physiological condition. A mismatch between action potential (AP) repolarization and relaxation of the contraction can be caused by intracellular Ca 2+ transport abnormalities. Ca 2+ influx via reverse activation of NCX can load the sarcoplasmic recticulum (SR), which has arrhythmogenic effect.Methods We studied the single myocytes from the left ventricle of adult mongrel dogs. During the cell separation, collagenase was perfused through LAD by Langandorff system. We use the patch-clamp system to determinded AP in current clamp mode. Myocyte contraction was imaged by a video camera, shortening of unloaded myocytes was detected by a video edge motion detector, using changes in light intensity at the edges of the myocyte. Results From 60 consecutive recorded APs at a constant 1.0 Hz stimulation under steady state conditions we found there is a variance in the repolarization between 10mV and-40mV. We also found the variance in the APD during the rate adaptation range of repolarization. Fluctuation in the transient may contribute to the APD variability. To test thishypothesis we block the transient by intracellular dialysis with 10 mM EGTA(n=19), this caused a significant reduction in the coefficient variability (CV=SD/mean APD%) from 2.3± 0.8 to 1.3± 0.3 P< 0.01. During a rate change of the stimulation from 0.6 Hz to 1.0 Hz. The AP duration increased from 278±8 msec to 320±9 msec, Mean+SD, n=5, 50 APs, P< 0.05. contraction is accompanied by an after-contraction(A-CON). The relaxation of contraction precedes the repolarization of the AP. We assumed that the enhancement of repolarization and the production of after-contraction can be possibly induced by reverse mode of NCX. Reducing [Na +] o by substitution of 40mM Na + with Li + favors NCX activating the reverse mode, which significantly decreased the dome of the AP from 4.8± 0.3 to -10.6± 1.2mV, P< 0.05, and increased the APD from 330±13 to 368±14 msec. P< 0.05.Conclusions Intracellular calcium transient most likely contributes to the beat-to-beat variance of action potential duration in canine ventricular myocyte. And it attributes to the voltage-dependent switch of NCX mode. Calcium concentration is high inmyocytes during the repolarization, and high intracellular Ca 2+ activates NCX in such a manner, that it generates an inward (positive, depolarizing) current. This current works against the repolarization, it is prolonging it, with other words it increases the duration of the action potential. The magnitude of calcium concentration during repolarization is very much dependent on calcium transport in the SR. The calcium transport in the SR is subject to adrenergic actions, and other physiologic and pathologic regulators. Under pathologic conditions

Association between ventricular repolarization variables and cardiac diastolic function: A cross-sectional study of a healthy Chinese population

BACKGROUND Diastolic electromechanical couple, a well-described phenomenon in symptomatic heart failure, has not been well studied in healthy people. We hypothesized that ventricular repolarization variables, such as the QT interval,Tpeak-to-Tend(Tpe) interval and Tpe/QT ratio, are associated with cardiac diastolic function in the healthy Chinese population.AIM To assess the relationship between ventricular repolarization variables and cardiac diastolic function in apparently healthy Chinese individuals.METHODS This was a community-based cross-sectional study conducted in Shenyang,China. A total of 414 healthy subjects aged 35-91 years were enrolled. All subjects underwent standard 12-lead electrocardiography(ECG) and comprehensive echocardiography. ECG enabled the measurement of QT and Tpe intervals and Tpe/QT ratio. echocardiographic parameters, such as the ratio of mitral early diastolic inflow velocity(E) and late diastolic inflow velocity(A), E-wave deceleration time, left atrial volume(LAV) and LAV index, were measured to assess diastolic function. E/A < 0.75 was considered to indicate reduced diastolic function. ECG and echocardiography results were analyzed separately and in a blinded fashion. Correlation and regression analyses were applied to determine associations.RESULTS Ventricular repolarization variables, such as the QTc interval(393.59 ± 26.74 vs403.86 ± 33.56; P < 0.001), Tpe interval(72.68 ± 12.41 vs 77.26 ± 17.86; P < 0.01),Tpec interval(76.36 ± 13.53 vs 83.32 ± 21.25; P < 0.001) and Tpe/QT ratio(0.19 ±0.03 vs 0.20 ± 0.04; P < 0.01), were significantly different between the normal diastolic function group and the reduced diastolic function group. Significant associations were found between repolarization variables and diastolic function.After adjusting for all other possible confounders, the QTc and Tpe_c intervals were significantly associated with the E/A ratio(P = 0.008; P = 0.010). In men, the QTc interval was associated with abnormal diastolic function, and compared to the third QTc tertile, in the second QTc tertile, the odds ratio was 0.257(95%CI:0.102–0.649; P = 0.004).CONCLUSION Repolarization variables are associated with cardiac diastolic function even in healthy people. Moderate levels of the QTc interval exert a protective effect on diastolic dysfunction in men.

Syncope and Early Repolarization:A Benign or Dangerous ECG Finding?

Early repolarization is a well-described,common electrocardiographic variant.It was initially felt to be benign,but in the last twenty years a suggested a link between specific types of early repolarization and sudden cardiac death has emerged.This association was has been termed the J wave syndrome and includes both the high risk early repolarization and Brugada ECG patterns.The odds of early repolarization change being associated with poor outcomes are still exceedingly small.Nevertheless,the association of a fairly ubiquitous ECG finding with fatal or near fatal clinical outcomes has raised concern.How can we identify the truly high-risk patients?If a patient has a signifi cant clinical event with a concerning ECG repolarization pattern,what should be done next?The authors of this review present current information regarding the Early Repolarization and Brugada Syndromes and how to proceed with diagnosis,management,and risk stratifi cation when early repolarization change is observed on ECG.

Effect of Calcium-Channel Antagonist on Repolarization Heterogeneity of Ventricular Myocardium in an in Vitro Rabbit Model of Long QT Syndrome

Intracellular Ca2＋ and Ca2＋-dependent signaling molecule play an essential role in the genesis of long-QT （LQT） syndrome-related ventricular arrhythmias. The effect of calcium-channel antagonist verapamil on repolarization heterogeneity of ventricular myocardium was assessed in an in vitro rabbit model of LQT syndrome. By using the monophasic action potential （MAP） recording technique, MAPs of epicardium, mid-myocardium and endocardium were simultaneously recorded by specially designed plunge-needle electrodes across the left ventricular free wall in rabbit hearts purfused by Langendorff method with standard Tyrode＇s solution. Bradycardia was induced by com- plete ablation of atrioventricular node. A catheter was introduced into the right ventricle to pace at the cycle lengths （CLs） of 1500, 1000, and 500 ms, successively. Quinidine （2 μmol/L） prolonged QT interval and ventricular MAP duration （MAPD）, and increased transmural dispersion of repolarization （TDR） in a reverse rate-dependent fashion in isolated rabbit heart. No polymorphic ventricular tachycardias were induced under this condition. The effective free therapeutic plasma concentrations of verapamil （0.01--0.05μmol/L） used in this experiment had no effect on quinidine-induced changes of QT interval, MAPD and TDR. This study demonstrated that, in this model of LQT syndrome, blockade of calcium-channel with verapmil had no effect on quinidine-induced changes of repolatiation heterogeneity of ventricular myocardium.

Ventricular Repolarization: Epidemiology and Clinical Correlates among Type-2 Diabetics with Uncontrolled Arterial Hypertension in Western Region of the Republic of Macedonia

This study aimed to describe the epidemiology of repolarization dispersion (QT dispersion and Tpeak-Tend dispersion) and further describe their associated clinical correlates among uncontrolled arterial hypertension in type-2 Diabetics patient, in western region of the Republic of Macedonia. Abnormal ventricular repolarization is associated with increased cardiovascular risk. Data relating to the frequency of increased repolarization dispersion, among uncontrolled arterial hypertension in type-2 Diabetics patient in western region of the Republic of Macedonia, are scarce. A total of 600 patients were enrolled into this observation study. Study participans were selected among primary care patient, who were receiving ongoing care for diabetes mellitus and hypertension during 1 calendar year. Twelve lead resting electrocardiography, QT, QTc, Tpeak-Tend-intervals and dispersions, were determined manually, and were compared between groups. Patients with uncontrolled BP have greater frequency of: prolonged QTc.max.interval, (61.3% vs.33.6%;p = 0.0005), prolonged Tpeak-Tend interval (65.3% vs. 34.7%;p = 0.005), increased dispersion of QTc. interval (65.9% vs. 34.1%;p = 0.00), increased disperion of Tpeak-Tend interval (65.5% vs. 34.5%;p = 0.002). Females with uncontrolled BP have greater frequency of: increased dispersion of QTc. interval (61.2% vs. 38%;p = 0.02), increased dispersion of Tpeak-Tend interval (63.1% vs. 31.5%;p = 0.008). Hypertensive diabetic patients with uncontrolled BP and abnormal ventricular repolarization have greater BMI (p = 0.000;95%CI 3.849 - 7.871), longer duration of D.M (p = 0.000;95%CI 1.600 - 1.981), longer duration of arterial hypertension (p = 0.000;95%CI 1.468 - 1.850) and less controlled glycemia (p = 0.000;95%CI 1.556 - 3.004). Frequency of increased set of electrophysiological parameters that indicate a prolonged and more heterogeneous repolarization among diabetic patients with uncontrolled BP, is considerable high and seems to be significantly associated with demographic and clinical parameters: gender, BMI, duration of diabetes, duration of BP and glycemic control.

Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy

cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Clinical frontiers in electrocardiographic early repolarization syndrome： does a good guy turn bad now？

Early repolarization pattern （ERP） is a common electrocardiographic （ECG） variant, characterized by J point elevation manifested either as QRS slurring （at the transition from the QRS segment to the ST segment） or notching （a positive deflection inscribed on terminal S wave）, ST-segment elevation with upper concavity and prominent T waves in at least two contiguous leads, The prevalence of ERP in normal population varies from 1% to 13%, depending on the age （predominant in young adults）, the race （highest amongst black oooulation）,

Heart rate profile during exercise in patients with early repolarization

Background Both early repolarization and altered heart rate profile are associated with sudden death. In this study, we aimed to demonstrate an association between early repolarization and heart rate profile during exercise.Methods A total of 84 subjects were included in the study. Comparable 44 subjects with early repolarization and 40 subjects with normal electrocardiogram underwent exercise stress testing. Resting heart rate, maximum heart rate, heart rate increment and decrement were analyzed.Results Both groups were comparable for baseline characteristics including resting heart rate. Maximum heart rate, heart rate increment and heart rate decrment of the subjects in early repolarization group had significantly decreased maximum heart rate, heart rate increment and heart rate decrement compared to control group （all P〈0.05）. The lower heart rate increment （〈106 beats/min） and heart rate decrement （〈95 beats/min） were significantly associated with the presence of early repolarization. After adjustment for age and sex, the multiple-adjusted OR of the risk of presence of early repolarization was 2.98 （95% CI 1.21-7.34） （P=0.018） and 7.73 （95% CI 2.84-21.03） （P 〈0.001） for the lower heart rate increment and heart rate decrement compared to higher levels, respectively.Conclusions Subjects with early repolarization have altered heart rate profile during exercise compared to control subjects. This can be related to sudden death.

Repolarization reserve, arrhythmia and new drug development

Repolarization-related lethal arrhythmias have led to the concept of“repolarization reserve”,which may help elucidate the relationship between K^(+) currents and other components of repolarization.Pharmacological manipulation as well as congenital and cardiac disease may affect repolarization and alter the repolarization reserve,leading to the development of arrhythmias.Pharmacological enhancement of outward currents or suppression of inward currents has been shown to be of therapeutic value.A number of newly found selective ion channel inhibitors or agonists have been investigated for their ability to enhance repolarization reserve and decrease the incidence of arrhythmia.In this paper we review the development,potential mechanisms,clinical application,and pharmacological significance of repolarization reserve in order to better understand,predict and prevent unexplained adverse cardiac events.